EP1183256B1 - Derives de la purine, leur procede de preparation, et compositions pharmaceutiques les contenant - Google Patents

Derives de la purine, leur procede de preparation, et compositions pharmaceutiques les contenant Download PDF

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EP1183256B1
EP1183256B1 EP00929625A EP00929625A EP1183256B1 EP 1183256 B1 EP1183256 B1 EP 1183256B1 EP 00929625 A EP00929625 A EP 00929625A EP 00929625 A EP00929625 A EP 00929625A EP 1183256 B1 EP1183256 B1 EP 1183256B1
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formula
radical
trans
amino
aminocyclohexyl
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EP1183256A1 (fr
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Jean-Luc Haesslein
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Aventis Pharma SA
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Aventis Pharma SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom

Definitions

  • the present invention relates to novel purine derivatives, process for their preparation, novel intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the novel use of such purine derivatives.
  • the invention thus relates to novel purine derivatives having anti-proliferative properties and in particular purine derivatives endowed with an inhibitory effect vis-à-vis cyclin-dependent protein kinases or 'cdk' abbreviated as we will use in the rest of the text.
  • Cdk are proteins consisting of at least two subunits, a catalytic subunit (of which cdc2 is the prototype) and a regulatory subunit (cyclin). We thus know a number of cdk. The cdk thus form protein complexes each of which is involved in a phase of the cell cycle.
  • kinase inhibitors have been described as butyrolactone, flavopiridol and 2 (2-hydroxyethylamino) -6-benzylamino-9-methylpurine called olomoucine.
  • the addition salts with the inorganic or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids.
  • stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position, and the different possible rotational conformations of the ethane derivatives.
  • stereoisomerism due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called geometric isomerism or cis-trans isomerism.
  • stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
  • R 2 is cyclopentyl
  • the radical R 2 represents, in particular, an alkyl, cycloalkyl, tetrahydrofuryl or tetrahydrothienyl radical.
  • the products of formula (IV) are subjected according to route 2) to the action of the product of formula (VI) as defined above in which Z represents -SO 2 , in particular in THF, DME, Cs 2 CO 3 , K 2 CO 3 or Na 2 CO 3 to give a product of formula (IX) as defined above.
  • the products of formula (IV) are subjected according to route 3 to the action of the product of formula (VII) as defined above in which Z represents the radical - (CH 2 ) 2 NHR 3 -, in particular in butanol at a temperature of about 75 ° C for about 2 or 3 hours to give a product of formula (X) as defined above.
  • the product of formula (X) thus obtained may be subjected to the action of a product of formula (XI) or (XI) A as defined above in DME, Cs 2 CO 3 or CH 2 Cl 2 and N (Et) 3 for about an hour at room temperature to give respectively a product of formula (XII) or (XII) A as defined above.
  • the product of formula (X) may also be subjected to the action of an aldehyde of formula (XVII) in particular in an alcohol such as methanol or ethanol, in presence of NaBH 4 or NaBH 3 CN. to give a product of formula (XIII) as defined above.
  • the corresponding products are prepared according to route 4 of the process as follows: the products of formula (IV) are subjected according to route 4 to the product of formula (XVIII) in which Z represents CO to give a product of formula (M 1 ) as defined above.
  • reaction of the product of formula (IV) with the product of formula (XVIII) can be carried out under the same conditions as those of the reaction of the product of formula (IV) with the product of formula VI to give the product of formula (IX ) in which when Z is SO 2 .
  • the products of formula (Ix) are therefore products of formula (I) in which the optionally reactive functional groups are optionally protected and in which Y represents -NR 5 - as defined above.
  • the products of formula (Iy) are therefore products of formula (I) in which the optionally reactive functions are optionally protected and in which Y represents -O- as defined above.
  • the saponification reaction can be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide.
  • a solvent such as methanol or ethanol, dioxane or dimethoxyethane
  • the products of formulas (Ix) and (Iy) constitute or not products of formula (I) and can give products of formula (I), or be converted into other products of formula (I) by being subjected to one or more of reactions a) to k) indicated above.
  • the products of the present invention as defined above possess kinase inhibitory properties of high selectivity.
  • CDKs play a central role in the initiation, development and completion of cell cycle events and thus, cdk inhibitory molecules are likely to limit unwanted cell proliferations such as those seen in cancers, psoriasis, growth fungi, parasites (animals, protists): such cdk inhibitory molecules are also likely to be involved in the regulation of neurodegenerative diseases such as Alzheimer's disease.
  • Kinases particularly sensitive to the inhibitory effects of the derivatives of the present invention include cdk1, cdk2, cdk4, cdk5 and cdk7.
  • the products of the present invention are therefore endowed with antimitotic properties.
  • the products of the present invention possess, in addition to their kinase-specific inhibitory properties, interesting cellular effects such as antiproliferative properties and in particular effects on apoptosis.
  • the products of the present invention are especially useful for tumor therapy.
  • the products of the invention can also increase the therapeutic effects of commonly used anti-tumor agents.
  • the products of formula (I) of the present invention therefore very particularly have antimitotic and anti-neurodegenerative properties.
  • the medicaments which are the subject of the invention find, for example, as antimitotics, their use in the chemotherapy of cancers, or in the treatment of psoriasis, parasitosis such as those due to protists or fungi, or in the treatment of Alzheimer's disease or in the treatment of neuronal apoptosis.
  • the invention extends to pharmaceutical compositions containing, as active ingredient, at least one of the medicaments as defined above.
  • compositions of the present invention may also, if appropriate, contain active ingredients of other antimitotic drugs such as in particular those based on taxol, cis-platinum, intercalating agents of DNA and others.
  • compositions may be administered orally, parenterally or locally by topical application to the skin and the skin. mucous membranes or by intravenous or intramuscular injection.
  • compositions may be solid or liquid and may be in any of the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, pills, lozenges, capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods.
  • the active ingredient can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, the fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, preservatives.
  • the usual dosage, variable according to the product used, the subject treated and the condition in question, may be, for example, from 0.05 to 5 g per day in the adult, or preferably from 0.1 to 2 g. per day.
  • the starting material of formula (II) is 2,6-dichloro-purine is known and marketed.
  • trans-1,4-diaminocyclohexane or trans-4-aminocyclohexanol there may be mentioned trans-1,4-diaminocyclohexane or trans-4-aminocyclohexanol.
  • the subject of the present invention is finally, as new industrial products, the compounds of formulas (IX), (X), (XII), (XII) A , (XIII) and (M 1 ).
  • the subject of the invention is therefore particularly pharmaceutical compositions containing as a active ingredient, at least one of the drugs as defined above.
  • the subject of the invention is particularly the pharmaceutical compositions as defined above, characterized in that they are used as antimitotic drugs, in particular for the chemotherapy of cancers or for the treatment of psoriasis, of parasitoses such as those due to to fungi or protists or Alzheimer's disease.
  • the invention also particularly relates to the pharmaceutical compositions as defined above, characterized in that they are used as antineurodegenerative drugs including neuronal anti-apoptosis.
  • the subject of the invention is in particular the use of the products of formula (I) as defined above for the preparation of medicaments intended for the chemotherapy of cancers, the treatment of psoriasis, parasitoses such as those due to fungi or protists, the treatment of Alzheimer's disease or the treatment of neurodegenerative diseases including neuronal apoptosis.
  • Step 2 Methyl 4 - [[(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -methyl] -benzoate
  • Step 3 Butyl trans-4 - [[[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] methyl] -benzoate dihydrochloride.
  • Step 1 (+ -) - 2,6-dichloro-9- (tetrahydro-3-furanyl) -9H-purine.
  • Step 2 (+ -) - 2-chloro-N- (phenylmethyl) -9- (tetrahydro-3-furanyl) -9H-purin-6-amine.
  • Step 3 Trans (+ -) - N2- (4-aminocyclohexyl) -N6- (phenylmethyl) -9- (tetrahydro-3-furanyl) -9H-purine-2,6-diamine dihydrochloride.
  • PRODUCT 3 Trans-N2- (4-aminocyclohexyl) -9- (1-ethylpropyl) -N6- (phenylmethyl) -9H-purine-2,6-diamine trans-N2- (2-aminocyclohexyl) -2,3-dihydroxybutanedioate.
  • Step 1 2,6-dichloro-9- (1-ethylpropyl) -9H-purine.
  • Step 2 2-Chloro-9- (1-ethylpropyl) -N- (phenylmethyl) -9H-purin-6-amine.
  • Step 3 trans-N2- (4-aminocyclohexyl) -9- (1-ethylpropyl) -N6- (phenylmethyl) -9H-purine-2,6-diamine trans-N2- (2-aminocyclohexyl) -2,3-dihydroxybutanedioate.
  • Step 1 2-chloro-9-cyclopentyl-N- (phenylmethyl) -9H-purin-6-amine.
  • Step 2 trans-9-Cyclopentyl-N2- (4-hydroxycyclohexyl) -N6- (phenylmethyl) -9H-purine-2,6-diamine hydrochloride.
  • trans-1,4-aminocyclohexanol 1 g is mixed and brought to a temperature of 50 to 60 ° C. and 212 mg of the product obtained in Stage 1 above are added and brought to a temperature of 140 to 150 ° C. for about 4 hours. It is then allowed to return to a temperature of 100 ° C., add 10 ml of water, leave to settle, add 10 ml of water, 20 ml of ethyl acetate and bring it to a temperature of about 70 ° C. 10 ml of water are then added and left overnight at room temperature.
  • the mixture is then decanted, re-extracted with 2 ⁇ 20 ml of methylene chloride containing 20% of methanol, the organic phases are combined, washed with 10 ml of water and 10 ml of saturated aqueous sodium chloride, dried and evaporated. dried up. It is then dissolved in ethanol minimum, added to 1.4N hydrochloric acid in ethanol and allowed to crystallize. It is diluted in 5 ml of ethanol and then left for one hour at room temperature. The mixture is filtered off with suction, washed with 10 ml of ethanol and dried at a temperature of approximately 50.degree. 215 mg of expected product are thus obtained in the form of white crystals.
  • Step 1 2,6-dichloro-9- (tetrahydro-3-thienyl) -9H-purine.
  • Step 2 2-Chloro-N- (phenylmethyl) -9- (tetrahydro-3-thienyl) -9H-purin-6-amine.
  • Step 3 Trans (+ -) - N2- (4-aminocyclohexyl) -N6- (phenylmethyl) -9- (tetrahydro-3-thienyl) -9H-purine-2,6-diamine dihydrochloride.
  • Step 1 4 - Ethyl [(2-chloro-9-cyclopentyl-9H-purin-6-yl) amino] benzoate.
  • Step 2 Ethyl trans-4 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] benzoate dihydrochloride.
  • Step 1 N- (2-aminoethyl) -2-chloro-9-cyclopentyl-9H-purin-6-amine.
  • Step 2 2-Chloro-9-cyclopentyl-N- [2 - [(phenylmethyl) amino] ethyl] -9H-purin-6-amine.
  • Step 3 trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [2 - [(phenylmethyl) amino] ethyl] -9H-purine-2,6-diamine trihydrochloride.
  • Step 3 of Example 1 The procedure is as in Step 3 of Example 1 from 0.090 g of the product obtained in Step 2 above, 277 mg of trans-1,4-diaminocyclohexane, heated at about 140 ° C for 2 hours. Purified on silica cartridge with CH 2 Cl 2 / methanol / ammonia in a ratio of 85/15 / 1.5. The product is salified for HCl solution in 1.4N EOOH. In this way 70 mg of expected product is obtained.
  • Step 1 N - [[2-chloro-9-cyclopentyl-9H-purin-6-yl] amino] benzenesulfonamide.
  • Step 2 Trans-N- [2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] benzenesulfonamide dihydrochloride.
  • PRODUCT 9 Trans (+ -) - N2- (4-aminocyclohexyl) -9- (1-methylpropyl) -N6- (phenylmethyl) -9H-purine-2,6 (2R, 3S) -2,3-dihydroxybutanedioate diamine.
  • Step 1 (+ -) - 2,6-dichloro-9- (1-methylpropyl) -9H-purine
  • Step 2 (+ -) - 2-chloro-9- (1-methylpropyl) -N- (phenylmethyl) -9H-purin-6-amine.
  • Step 2 of Example 3 The procedure is as in Step 2 of Example 3 and 161 mg of the product obtained in Step 1 above, 3 ml of butanol and 0.132 ml of benzylamine are added and the mixture is heated at a temperature of about 90 to 110 ° C. for about 5 hours. hours. The mixture is then allowed to return to ambient temperature, allowed to crystallize, diluted with 10 ml of isopropanol, filtered off, washed with 10 ml of isopropanol and dried under vacuum at approximately 50.degree. After chromatography on silica eluting with methylene chloride / ethyl acetate in a proportion of 50/50, 179 mg of expected product are obtained in the form of white crystals.
  • Stage 3 (2R, 3S) -2,3-dihydroxybutanedioate of trans (+ -) -N2- (4-aminocyclohexyl) -9- (1-methylpropyl) -N6- (phenylmethyl) -9H-purine-2,6 diamine.
  • Step 3 of Example 3 The procedure is as in Step 3 of Example 3 and carries 388 mg of trans-1,4-diaminocyclohexane at a temperature of 150 ° C and adds 107 mg of the product obtained in Step 2 above and leaves at a temperature of 140. at 150 ° C for about 17 hours then allow to return to room temperature. Then taken up with 10 ml of ethyl acetate / water in a proportion of 50/50, decanted, re-extracted with 2 x 10 ml of ethyl acetate, washed with 10 ml of water and 5 ml of saturated aqueous sodium chloride solution, dried and evaporated to dryness.
  • EXAMPLE 10 dihydrochloride of trans-N- (2 - ((2 - ((4-aminocyclohexyl) amino) -9-cyclopentyl-9H-purin-6-yl) -amino) ethyl) -4-methyl-benzenesulfonamide.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -4-methyl-benzenesulfonamide.
  • Step 2 Trans-N- (2 - ((2 - ((4-aminocyclohexyl) amino) -9-cyclopentyl-9H-purin-6-yl) -amino) -ethyl) -4-methyl-benzenesulfonamide dihydrochloride.
  • Step 1 (+ -) - 4 - [[2-chloro-9- (tetrahydro-3-furanyl) -9H-purin-6-yl] amino] benzoate.
  • Step 2 of Example 2 The procedure is as in Step 2 of Example 2 starting from 181 mg of the product obtained in Step 1 of Example 2 and 3 ml of butanol and using 124 ml of ethyl 4-aminobenzoate instead of benzylamine. . 214 mg of expected product are thus obtained in the form of white crystals.
  • Step 2 Ethyl trans (+ -) [[2 - [(4-aminocyclohexyl) amino] -9- (tetrahydro-3-furanyl) -9H-purin-6-yl] amino] benzoate dihydrochloride .
  • Step 1 (+ -) - 2-chloro-N - [(3-iodophenyl) methyl] -9- (tetrahydro-3-furanyl) -9H-purin-6-amine.
  • Step 2 of Example 2 The procedure is as in Step 2 of Example 2 starting from 133 mg of the product obtained in Step 1 of Example 2 and 2 ml of butanol and using 0.2 mg of 3-iodo-benzenemethanamine (1.1 eq. ) instead of benzylamine. 208 mg of expected product is thus obtained in the form of white crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -N6 - [(3-iodophenyl) methyl] -9- (tetrahydro-3-furanyl) trans (+ -) - N2- (2-aminocyclohexyl) -2,3-dihydroxybutanedioate -9H-purine-2,6-diamine.
  • Example 6 240 mg of the product of Example 6, 10 ml of ethanol and then 1 ml of sodium hydroxide (+ -) - 2-chloro-N-propyl-9- (tetrahydro-3-furanyl) -9H-purin-6-amine, stirred at room temperature for about 20 hours, heated to about 95 ° C for about 3 hours and then left overnight at room temperature and then evaporated to dryness. It is impasted in acetic acid and then ether, dried at approximately 50 ° C. and thus obtains 244 mg of expected product in the form of beige crystals.
  • Step 1 (+ -) - 2-chloro-N-propyl-9- (tetrahydro-3-furanyl) -9H-purin-6-amine.
  • Step 2 of Example 2 The procedure is as in Step 2 of Example 2 starting from 181 mg of the product obtained in Step 1 of Example 2 and 3 ml of butanol and using 0.062 ml of 1-propanamine instead of benzylamine. 136 mg of expected product are thus obtained in the form of beige crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -N6-propyl-9- (tetrahydro-3-furanyl) -9H-purine-2,6-diamine dihydrochloride.
  • Step 3 of Example 2 The procedure is as in Step 3 of Example 2 starting from 109 mg of the product obtained in Step 1 above and 445 mg of trans-1,4-diaminocyclohexane. After purification on silica eluting with methanol / ammonia (NH 4 OH) in a proportion of 98/2, salified with 1.4N hydrochloric acid in ethanol. In this way 78 mg of expected product is obtained in the form of crystals.
  • methanol / ammonia NH 4 OH
  • Step 1 N - [[2-chloro-9-cyclopentyl-9H-purin-6-yl] amino] -4- (1-methylethyl) -benzenesulfonamide.
  • Step 1 of Example 8 The procedure is as in Step 1 of Example 8 and mixing 257 mg of the product obtained in Step 1 of Example 1, 4 ml of dimethoxyethane (DME), 390 mg of cesium carbonate (CS 2 CO 3 ) and 199 mg of 4- (1-methylethyl) -benzenesulfonamide in place of benzenesulfonamide and stirred at a temperature of about 100 ° C for about 2 hours 30 minutes. Allowed to warm to room temperature, acidified with 4 ml of 2N hydrochloric acid, extracted with 2 x 10 ml of ethyl acetate, dried and evaporated to dryness. It is crystallized from 5 ml of ether, drained and dried at room temperature. 187 mg of expected product are thus obtained in the form of colorless crystals.
  • DME dimethoxyethane
  • CS 2 CO 3 cesium carbonate
  • Step 2 Trans-N- [2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] -4- (1-methylethyl) -benzenesulfonamide dihydrochloride.
  • the process is carried out as in Stage 2 of Example 8 and carries 456 mg of trans-1,4-diaminocyclohexane at a temperature of approximately 150 ° C., adds 168 mg of the product obtained in Stage 1 above and temperature of 150 ° C for about 3 hours 30 minutes then allow to return to room temperature.
  • 5 ml of ethanol / 1.4N hydrochloric acid are dissolved in 5 ml of ethanol, evaporated to dryness and pasted in 5 ml of ether to give 42 mg of expected product in the form of crystals.
  • Step 1 2-Chloro-9-cyclopentyl-N- [2 - [[(4-methoxyphenyl) methyl] amino] ethyl] -9H-purin-6-amine.
  • Step 2 of Example 7 The procedure is as in Step 2 of Example 7 starting from 280 mg of the product obtained in Step 1 of Example 7, 4 ml of methanol, 0.2 ml of 4-methoxy-benzaldehyde, 0.2 ml of acetic acid and 100 mg NaBH 3 CN and stirred at room temperature for about 6 hours. 10 ml AcOEt are added, the mixture is washed with 2 ⁇ 5 ml H 2 O and then 5 ml of a saturated aqueous solution of NaCl. The solvent is dried and evaporated after chromatography on silica eluting with CH 2 Cl 2 / methanol / aqueous ammonia in a proportion of 90/10/1. 208 mg of expected product is thus obtained.
  • Step 2 Trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [2 - [[(4-methoxyphenyl) -methyl] -amino] -ethyl] -9H-purine-2,6-diamine trihydrochloride .
  • Step 3 of Example 7 starting from 186 mg of the product obtained in Stage 1 above, 490 mg of trans-1,4-diaminocyclohexane is heated at approximately 140 ° C. for 10 hours. Purify on silica with eluent CH 2 Cl 2 / MeOH / NH 4 OH (85/15 / 1.5) then salified with a solution of 1.4N hydrochloric acid in ethanol. In this way 60 mg of expected product is obtained.
  • Step 1 2-chloro-9-cyclopentyl-N- [2 - [[(7-methoxy-1,3-benzodioxol-5-yl) -methyl] -amino] -ethyl] -9H-purin-6-amine .
  • Step 2 of Example 7 The procedure is as in Step 2 of Example 7 starting from 280 mg of the product obtained in Step 1 of Example 7, 4 ml of methanol, 250 mg of 7-methoxy-1,3-benzodioxole-5-carboxaldehyde. place benzaldehyde, 0.2 ml acetic acid and 0.4 ml tetrahydrofuran and leave for 4 hours at room temperature. 100 mg is then added of NaBH3CN and stirred at room temperature for about 3 hours. 10 ml AcOEt are added, the mixture is washed with 2 ⁇ 5 ml H 2 O and then 5 ml aqueous solution saturated with NaCl. The solvent is dried and evaporated. After purification by chromatography on silica eluting with methylene chloride / methanol / ammonia in a proportion of 90/10/1, 311 mg of expected product is obtained in the form of beige crystals.
  • Step 2 Trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [2 - [[(7-methoxy-1,3-benzodioxol-5-yl) -methyl] -amino] -ethyl trihydrochloride] -9H-purine-2,6-diamine.
  • Step 3 of Example 7 starting from 65 mg of the product obtained in Stage 1 above, 743 mg of trans-1,4-diaminocyclohexane is heated at about 140 ° C. for 3 hours. It is treated with 10 ml of water and extracted with 2 ⁇ 10 ml of ethyl acetate, washed with 10 ml of NaCl (saturated aqueous solution) and dried over MgSO 4 . Salted with 1.4N HCl / EtOH, washed with 5 ml EtOH and then dried at ⁇ 50 ° C. 161 mg of expected product is thus obtained.
  • Step 1 2-Chloro-N- [2 - [[[4-chloro-3- (trifluoromethyl) -phenyl] -methyl] -amino] -ethyl] -9-cyclopentyl-9H-purin-6-amine.
  • Step 2 of Example 7 The procedure is as in Step 2 of Example 7 starting from 280 mg of the product obtained in Step 1 of Example 7, 4 ml of methanol, 292 mg of 4-chloro-3- (trifluoromethyl) benzaldehyde in place of benzaldehyde and 0.2 ml of acetic acid and then stirred at room temperature for about 3 hours. 100 mg of 3N NaBH 3 are then added and the mixture is stirred at room temperature for about 3 hours. 10 ml AcOEt are added, washed with 2 ⁇ 5 ml H 2 O and then 5 ml of saturated aqueous NaCl solution. The solvent is dried and evaporated. After purification by chromatography on silica eluting with methylene chloride / methanol / ammonia in a proportion of 90/10/1, 367 mg of expected product are obtained in the form of beige crystals.
  • Step 2 trans-N2- (4-aminocyclohexyl) -N6- [2 - [[[4-chloro-3- (trifluoromethyl) -phenyl] -methyl] -amino] -ethyl] -9-cyclopentyl-9H-trihydrochloride -purine-2,6-diamine.
  • Step 3 of Example 7 The procedure is as in Step 3 of Example 7 from 320 mg of the product obtained in Step 1 above and 770 mg of trans-1,4-diaminocyclohexane and heated at about 140 ° C for 3 hours. After purification by chromatography on silica with chlorine eluent methylene / methanol / ammonia in a proportion of 85/25 / 1.5 is salted with 1.4N HCl / EtOH, filtered, washed with 5 ml EtOH and then dried at ⁇ 50 ° C. 166 mg of expected product is thus obtained.
  • Step 1 2-Chloro-9-cyclopentyl-N- [2 - [(diphenylmethyl) amino] ethyl] -9H-purin-6-amine.
  • Step 2 of Example 7 The procedure is as in Step 2 of Example 7 starting from 141 mg of the product obtained in Step 1 of Example 7, 2 ml of methanol, 0.7 ml (15 eq) of benzaldehyde and 0.1 ml of acetic acid and then stirred at room temperature for about 3 hours. Then 55 mg of sodium cyanoborohydride (NaBH 3 CN) and stirred at room temperature for 1 hour. 10 ml of AcOEt are added, the mixture is washed with 2 ⁇ 5 ml H 2 O and then 5 ml of saturated aqueous NaCl solution. The solvent is dried and evaporated.
  • NaBH 3 CN sodium cyanoborohydride
  • Step 2 trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6 - [(diphenylmethyl) amino] ethyl] -9H-purine-2,6-diamine trihydrochloride.
  • Step 3 of Example 7 The procedure is as in Step 3 of Example 7 starting from 90 mg of the product obtained in Step 1 above and 222 mg of trans-1,4-diaminocyclohexane and heating at about 140 ° C for about 2 hours. After purification by chromatography on silica eluting with methylene chloride / methanol / ammonia in a proportion of 85/15 / 1.5, the mixture is salted with 1.4N HCl / EtOH, filtered, washed with 5 ml of EtOH and then dried at ⁇ 50 ° C. ° C.
  • Step 3 of Example 1 The procedure is as in Step 3 of Example 1 starting from 741 mg of trans-1,4-diaminocyclohexane which is heated to about 140 ° C. and then 500 mg of the product obtained in Step 2 of Example 1 are added and leave at this temperature for about 3 hours then allow to return to room temperature. 5 ml H 2 O is added and then filtered. The precipitate is taken up in 10 ml of ethanol and then 3 ml of 1.4N hydrochloric acid in ethanol is added, the insoluble material is filtered and the mixture is evaporated to dryness. The residue is impregnated with ether and dried at ambient temperature, thereby obtaining 45 mg of expected product.
  • Step 1 4 - Methyl [[[2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) amino] ethyl] amino] methyl] benzoate.
  • Step 2 of Example 7 The procedure is as in Step 2 of Example 7 starting with 280 mg of the product obtained in Step 1 of Example 7, 4 ml of methanol, 230 mg of methyl 4-formylbenzoate in place of the benzaldehyde and 2 ml of acetic acid and then stirred at room temperature for 5 hours. 100 mg of NaBH3CN are then added and the mixture is stirred at room temperature for approximately 1 hour. 10 ml AcOEt are added, the mixture is washed with 2 ⁇ 5 ml H 2 O and then 5 ml aqueous solution saturated with NaCl. The solvent is dried and evaporated. After purification by chromatography on silica eluting with methylene chloride / methanol / ammonia in a ratio of 95: 05: 0.5, 260 mg of expected product is obtained.
  • Step 2 Trans 4 - [[[2 [[2 - [(4-Aminocyclohexyl) -amino] -9-cyclopentyl-9H-purin-6-yl] -amino] -ethyl] -amino] -methyl trihydrochloride] methyl benzoate.
  • Step 3 of Example 7 The procedure is as in Step 3 of Example 7 from 256 mg of the product obtained in Step 1 above and 700 mg of trans-1,4-diaminocyclohexane and heated at about 140 ° C for about 4 hours. Then extracted with 3 x 10 ml of ethyl acetate and washed with 10 ml of saturated aqueous sodium chloride solution. After purification by chromatography on silica eluting with methylene chloride / methanol / ammonia in a proportion of 85/15 / 1.5, salified with 1.4N HCl / EtOH, washed with 5 ml EtOH and then dried at ⁇ 50 ° C. . In this way 70 mg of expected product is obtained.
  • Step 1 2-chloro-N- [2 - [[(4-cyanophenyl) methyl] amino] ethyl] -9-cyclopentyl-9H-purin-6-amine.
  • Step 2 of Example 7 The procedure is as in Step 2 of Example 7 starting from 280 mg of the product obtained in Step 1 of Example 7, 184 mg of 4-cyano-benzaldehyde in place of benzaldehyde, 4 ml of methanol and 0.2 ml of acetic acid and 0.5 ml of tetrahydrofuran and then stirred at room temperature for about 5 hours. 100 mg of NaBH 3 CN are then added and the mixture is stirred at room temperature for 1 hour. 10 ml AcOET is added, washed with 2 ⁇ 5 ml H 2 O and then 5 ml aqueous solution saturated with NaCl. The solvent is dried and evaporated. After purification by chromatography on silica eluting with methylene chloride / methanol / hydroxylamine in a ratio of 95: 05: 0.33, 347 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans-N2- (4-Aminocyclohexyl) -N6- [4-cyanophenyl) methyl] amino] ethyl] -9-cyclopentyl-9H-purin-2,6-diamine trihydrochloride.
  • Step 3 of Example 7 The procedure is as in Step 3 of Example 7 starting from 250 mg of the product obtained in Step 1 above and 720 mg. trans-1,4-diaminocyclohexane and heated at about 140 ° C for 4 hours. It is taken up in 10 ml H 2 O and then extracted with 3 ⁇ 10 ml of ethyl acetate and washed with 10 ml of saturated sodium chloride. After purification by chromatography on silica eluting with methylene chloride / methanol / hydroxylamine in a proportion of (85/15 / 1.5), salified with 1.4N HCl / EtOH, washed with 5 ml EtOH and then dried at -50. ° C. 222 mg of expected product is thus obtained.
  • Step 1 2-chloro-9-cyclopentyl-N- [2 - [[(3,4,5-trimethoxyphenyl) -methyl] -amino] -ethyl] -9H-purin-6-amine.
  • Step 2 of Example 7 The procedure is as in Step 2 of Example 7 starting from 280 mg of the product obtained in Step 1 of Example 7, 275 mg of 3,4,5-trimethoxybenzaldehyde in place of benzaldehyde, 4 ml of methanol and 0 2 ml of acetic acid and then stirred at room temperature for 5 hours. 100 mg of 3N NaBH 3 are then added and the mixture is stirred at room temperature for approximately 1 hour. 10 ml AcOEt are added, the mixture is washed with 2 ⁇ 5 ml H 2 O and then 5 ml aqueous solution saturated with NaCl. The solvent is dried and evaporated. After purification by chromatography on silica eluting with methylene chloride / methanol / ammonia in a ratio of 95: 05: 0.33, 305 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [2 - [[3,4-5-trimethoxyphenyl) -methyl] -amino] -ethyl] -9H-purin-2-trihydrochloride 6-diamine.
  • Step 3 of Example 7 The procedure is as in Step 3 of Example 7 from 297 mg of the product obtained in Step 1 above and 735 mg of trans-1,4-diaminocyclohexane and heated at about 140 ° C for 3 hours 30 minutes. Poured into 10 ml H 2 O and extracted with 3 x 10 ml of ethyl acetate and washed with 10 ml of saturated sodium chloride. After purification by chromatography on silica eluting with methylene chloride / methanol / ammonia in a proportion of 85/15 / 1.5, salified with 1.4N HCl / EtOH, washed with 5 ml EtOH and then dried at ⁇ 50 ° C. .
  • Step 1 2-chloro-N- [2 - [[(4-chlorophenyl) methyl] amino] ethyl] -9-cyclopentyl-9H-purin-6-amine.
  • Step 2 of Example 7 The procedure is as in Step 2 of Example 7 starting from 280 mg of the product obtained in Step 1 of Example 7, 197 mg of 4-chlorobenzaldehyde instead of benzaldehyde, 4 ml of methanol and 0.2 ml of Acetic acid then stirred at room temperature for 5 hours. 100 mg of 3N NaBH 3 are then added and the mixture is stirred at room temperature for approximately 1 hour. 10 ml AcOEt are added, the mixture is washed with 2 ⁇ 5 ml H 2 O and then 5 ml aqueous solution saturated with NaCl. The solvent is dried and evaporated. After purification by chromatography on silica eluting with methylene chloride / methanol / ammonia in a ratio of 95: 05: 0.33, 258 mg of expected product is obtained.
  • Step 2 Trans-N2- (4-aminocyclohexyl) -N6- [2 - [[(4-chlorophenyl) -methyl] -amino] -ethyl] -9-cyclopentyl-9H-purin-2,6-diamine trihydrochloride .
  • Step 3 of Example 7 The procedure is as in Step 3 of Example 7 from 242 mg of the product obtained in Step 1 above and 680 mg of trans-1,4-diaminocyclohexane and heated at about 140 ° C for about 3 hours 30 minutes. It is poured into H 2 O and then extracted with 3 ⁇ 10 ml of ethyl acetate and washed with 10 ml of saturated sodium chloride. After purification by chromatography on silica eluting with methylene chloride / methanol / ammonia in a proportion of 85/15 / 1.5, salified with 1.4N HCl / EtOH, washed with 5 ml EtOH and then dried at ⁇ 50 ° C. .
  • Step 1 3-Bromo-N - [[2-chloro-9-cyclopentyl-9H-purin-6-yl] amino] benzenesulfonamide.
  • Step 1 of Example 8 The procedure is as in Step 1 of Example 8 starting from 257 mg of the product obtained in Stage 1 of Example 1, 4 ml of dimethoxyethane (DME), 390 mg of cesium carbonate (Cs 2 CO 3 ) and 236 mg of 3-bromo-benzenesulfonamide in place of benzenesulfonamide and stirred at a temperature of about 100 ° C for about 2 hours 30 minutes. Allowed to warm to room temperature, acidified with 4 ml of 2N hydrochloric acid, extracted with 2 x 10 ml of ethyl acetate, dried and evaporated to dryness. It is impasted in 5 ml of ether, drained and dried at room temperature. 356 mg of expected product are thus obtained in the form of beige crystals.
  • DME dimethoxyethane
  • Cs 2 CO 3 cesium carbonate
  • 356 mg of expected product are thus obtained in the form of beige crystals.
  • Step 2 Trans-N- [2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] -3-bromo-benzenesulfonamide dihydrochloride.
  • Step 2 of Example 8 The procedure is as in Step 2 of Example 8 and carries 400 mg of trans-1,4-diaminocyclohexane at a temperature of about 150 ° C., add 319 mg of the product obtained in Step 1 above and maintain temperature of 150 ° C overnight. The mixture is then allowed to return to room temperature and then chromatographed on silica eluting with CH 2 Cl / MeOH / NH 4 OH (70/30/1), 4 ml of ethanol and 4 ml of ethanol / hydrochloric acid 1 are then added. 4N, evaporated to dryness, pasted in 10 ml of ether / ethyl acetate in a proportion of 50/50 and dried under vacuum at a temperature of about 50 ° C. 231 mg of expected product are thus obtained in the form of beige crystals.
  • Step 1 N - [[2-chloro-9-cyclopentyl-9H-purin-6-yl] amino] -3-trifluoromethyl-benzenesulfonamide.
  • Step 1 of Example 8 The procedure is as in Step 1 of Example 8 starting from 257 mg of the product obtained in Stage 1 of Example 1, 4 ml of dimethoxyethane (DME), 390 mg of cesium carbonate (Cs 2 CO 3 ) and 225 mg of 3-trifluoromethyl-benzenesulfonamide in place of benzenesulfonamide and stirred at a temperature of about 100 ° C for about 2 hours 30 minutes. Allowed to warm to room temperature, acidified with 4 ml of 2N hydrochloric acid, extracted with 2 x 10 ml of ethyl acetate, dried and evaporated to dryness. It is impasted in 10 ml of ether, filtered and dried at room temperature. In this way 273 mg of expected product is obtained in the form of colorless crystals.
  • DME dimethoxyethane
  • Cs 2 CO 3 cesium carbonate
  • 3-trifluoromethyl-benzenesulfonamide in place of benzenes
  • Step 2 Trans-N- [2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] -3- (trifluoromethyl) -benzenesulfonamide dihydrochloride.
  • Step 2 of Example 8 The procedure is as in Step 2 of Example 8 and carries 286 mg of trans-1,4-diaminocyclohexane, at a temperature of about 150 ° C., 222 mg of the product obtained is added. Stage 1 above and maintained at this temperature of 150 ° C for 3 hours, then at 110 ° C overnight and then at 150 ° C for 2 hours. It is then allowed to return to ambient temperature and then chromatographed on silica eluting with CH 2 Cl 2 / MeOH / NH 4 OH (70/30/1), then 5 ml of ethanol and 4 ml of ethanol / hydrochloric acid 1 are added.
  • Step 1 N - [[2-chloro-9-cyclopentyl-9H-purin-6-yl] amino] -4- (1,1-dimethylethyl) benzenesulfonamide.
  • Step 1 of Example 8 The procedure is as in Step 1 of Example 8 starting from 257 mg of the product obtained in Step 1 of Example 1, 4 ml of dimethoxyethane (DME), 390 mg of cesium carbonate (CS 2 CO 3 ) and 213 mg of 4- (1,1-dimethylethyl) -benzenesulfonamide in place of benzenesulfonamide and stirred at a temperature of about 100 ° C for about 4 hours. Allowed to warm to room temperature and added 4 ml of 2N hydrochloric acid and 5 ml of water, extracted with 40 ml of ethyl acetate, dried and evaporated to dryness. It is impasted in 10 ml of ether, filtered and dried at room temperature. 253 mg of expected product is thus obtained in the form of beige crystals.
  • DME dimethoxyethane
  • CS 2 CO 3 cesium carbonate
  • Step 2 Trans-N- [2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] -4- (1,1-dimethylethyl) benzenesulfonamide dihydrochloride.
  • Step 2 of Example 8 The process is carried out as in Step 2 of Example 8 and carries 286 mg of trans-1,4-diaminocyclohexane at a temperature of about 150 ° C., 217 mg of the product obtained in Step 1 above is added and maintained at this temperature. temperature for about 5 hours. The mixture is then allowed to return to ambient temperature and then chromatographed on silica, eluting with methylene chloride / methanol / aqueous ammonia in a proportion of 70/30/1.
  • Step 1 2-chloro-N-propyl-9- (tetrahydro-3-thienyl) -9H-purin-2,6-diamine.
  • Step 2 of Example 5 The procedure is as in Step 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.100 ml of 1-propanamine in place of benzylamine and a temperature of about 80 to 85 ° C for 24 hours. Allowed to warm to room temperature, evaporated to dryness, pasted in 10 ml of ethyl acetate at room temperature, filtered, washed with 10 ml and dried under vacuum at a temperature of about 50 ° C. 123 mg of expected product are thus obtained in the form of white crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -N6-propyl-9- (tetrahydro-3-thienyl) -9H-purin-2,6-diamine dihydrochloride.
  • Step 3 of Example 5 The procedure is as in Step 3 of Example 5 starting from 400 mg of trans-1,4-diaminocyclohexane and 106 mg of the product obtained in Step 1 above, brought to a temperature of approximately 140 to 145 ° C. for about 6 hours then allow to return to room temperature.
  • methanol / ammonia NH 4 OH
  • 30 mg of expected product are obtained in the form of beige crystals. pink.
  • Step 1 2-Chloro-N - [(3-iodophenyl) methyl] -9- (tetrahydro-3-thienyl) -9H-purin-6-amine.
  • Step 2 of Example 5 The procedure is as in Step 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.114 ml of 3-iodobenzenemethanamine in place of benzylamine and a temperature of about 80 to 85 ° C for about 30 hours. Allowed to warm to room temperature, diluted with 3 ml of isopropanol, place about one hour at a temperature of about 0 ° C, filtered, washed with 5 ml of isopropanol and dried under vacuum at a temperature of about 50 ° vs. After purification on silica eluting with methylene chloride / ethyl acetate 90/10, 173 mg of expected product are thus obtained in the form of white-yellow crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -N6 - [(3-iodophenyl) methyl] -9- (tetrahydro-3-thienyl) -9H-purin-2,6-diamine dihydrochloride .
  • Step 1 2-chloro-N-phenyl-9- (tetrahydro-3-thienyl) -9H-purin-6-amine.
  • Step 2 of Example 5 The procedure is as in Step 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.055 ml of aniline instead of benzylamine and gives temperature of about 80 to 85 ° C for 20 hours. Allowed to warm to room temperature, diluted with 5 ml of isopropanol, Place for about one hour at a temperature of about 0 ° C., drain, wash with 5 ml of isopropanol and dry under vacuum at a temperature of about 50 ° C. After purification on silica eluting with 90/10 proportion of methylene chloride / ethyl acetate, 173 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -N6-phenyl-9- (tetrahydro-3-thienyl) -9H-purin-2,6-diamine dihydrochloride.
  • Step 3 of Example 5 The procedure is as in Step 3 of Example 5 from 536 mg of trans-1,4-diaminocyclohexane and 156 mg of the product obtained in Step 1 above, brought to a temperature of about 140 to 145 ° C. for about 4 hours 30 minutes then allow to return to room temperature.
  • methanol / ammonia NH 4 OH
  • the mixture is filtered off, washed and dried at a temperature of 50 ° C.
  • 145 mg of expected product are thus obtained in the form of beige-beige crystals.
  • Step 1 4 - ((2-Chloro-9- (tetrahydro-3-thienyl) -9H-purin-6-yl) -amino) -benzoate.
  • Step 2 of Example 5 The procedure is as in Step 2 of Example 5 starting from 160 mg of the product obtained in Step 1 of Example 5, 3 ml of butanol and using 100 mg of ethyl 4-aminobenzoate instead of benzylamine. and is heated at a temperature of about 80 to 85 ° C for 30 hours. Allowed to warm to room temperature, diluted with 3 ml of isopropanol, place about one hour at a temperature of about 0 ° C, filtered, washed with 5 ml of isopropanol and dried under vacuum at a temperature of about 50 ° vs. After purification on silica eluting with 90/10 proportion of methylene chloride / ethyl acetate, 202 mg of expected product are obtained in the form of cream-white crystals.
  • Step 2 Trans (+ -) - 4 - [[2 - [(4-Aminocyclohexyl) -amino] -9- (tetrahydro-3-thienyl) -9H-purin-6-yl] -amino] -benzoate dihydrochloride ethyl.
  • Step 3 of Example 5 The procedure is as in Step 3 of Example 5 from 513 mg of trans-1,4-diaminocyclohexane which is heated to a temperature of about 70 to 75 ° C. and 181 mg of the product obtained in Step 1 are added. above, brought to a temperature of about 140 to 145 ° C for 4 hours 30 minutes then allowed to return to room temperature.
  • methanol / ammonia NH 4 OH
  • the mixture is filtered off with suction, washed with 10 ml of ethanol and dried at room temperature. a temperature of about 50 ° C. In this way 150 mg of expected product is obtained in the form of white crystals.
  • Step 1 2-chloro-9- (tetrahydro-3-thienyl) -N- [4- (trifluoromethoxy) -phenyl] -9H-purin-6-amine.
  • Step 2 of Example 5 The procedure is as in Step 2 of Example 5 starting from 160 mg of the product obtained in Step 1 of Example 5, 3 ml of butanol and using 0.081 ml of 4- (trifluoromethoxy) -benzenamine in place of the benzylamine and is heated at a temperature of about 80 to 85 ° C for about 20 hours. Allowed to warm to room temperature, diluted with 3 ml of isopropanol, place about 1 hour at a temperature of about 0 ° C, filtered, washed with 5 ml of isopropanol and dried under vacuum at a temperature of about 50 ° vs. After purification on silica eluting with 90/10 proportion of methylene chloride / ethyl acetate, 203 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -9- (tetrahydro-3-thienyl) -N6- [4- (trifluoromethoxy) -phenyl] -9H-purin-2,6-diamine dihydrochloride .
  • Step 1 (+ -) - 2-chloro-N-phenyl-9- (tetrahydro-3-furanyl) -9H-purin-6-amine.
  • Step 2 of Example 2 The procedure is as in Step 2 of Example 2 starting from 200 mg (0.77 mM) of the product obtained in Step 1 of Example 2 and 3 ml of butanol and using 0.088 ml of aniline (0.96 ml). mmol) instead of benzylamine. 213 mg of expected product are thus obtained in the form of white crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -N6-phenyl-9- (tetrahydro-3-furanyl) -9H-purine-2,6-diamine dihydrochloride.
  • Step 3 of Example 2 The procedure is as in Step 3 of Example 2 starting from 198 mg of the product obtained in Step 1 above and 716 mg of trans-1,4-diaminocyclohexane. After purification on silica eluting with methanol / ammonia (NH 4 OH) in a proportion of 98/2 and salification with 1.4N hydrochloric acid in ethanol, 169 mg of expected product are obtained in the form of beige-beige crystals.
  • methanol / ammonia NH 4 OH
  • Step 1 (+ -) - 2-chloro-9- (tetrahydro-3-furanyl) -N- [4- (trifluoromethoxy) -phenyl] -9H-purin-6-amine.
  • Step 2 of Example 2 The procedure is as in Step 2 of Example 2 starting from 200 mg (0.77 mmol) of the product obtained in Step 1 of Example 2 and 3 ml of butanol and using 0.130 ml of 4- (trifluoromethoxy) - benzenamine (0.96 mmol) instead of benzylamine. In this way 72 mg of expected product is obtained in the form of white crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -9- (tetrahydro-3-furalyl) -N6 - [(4-trifluoromethoxy) -phenyl] -9H-purin-2,6-diamine dihydrochloride .
  • Step 3 of Example 2 The procedure is as in Step 3 of Example 2 starting from 153 mg of the product obtained in Step 1 above and 433 mg of trans-1,4-diaminocyclohexane. After purification on silica eluting with methanol / ammonia (NH 4 OH) in a proportion of 98/2 and salification with 1.4N hydrochloric acid in ethanol, 114 mg of expected product are obtained in the form of white crystals. cream.
  • methanol / ammonia NH 4 OH
  • PRODUCT 36 Trans-N2- (4-aminocyclohexyl) -9- (1-ethylpropyl) -N6-propyl-9H-purin-2,6-diamine dihydrochloride. Step 1 : 2-chloro-9- (1-ethylpropyl) -N-propyl-9H-purin-6-amine.
  • Step 2 of Example 3 The procedure is as in Step 2 of Example 3 starting from 200 mg of the product obtained in Step 1 of Example 3 and 4 ml of butanol and using 0.129 ml of propylamine in place of benzylamine. It is stirred at ambient temperature and then brought to a temperature of 80 to 85 ° C. for 5 hours. Allowed to warm to room temperature, evaporated to dryness and then impasted in 5 ml of pentane at room temperature, filtered, washed and dried at a temperature of about 50 ° C. After purification on silica eluting with methylene chloride / ethyl acetate in a proportion of 90/10, 145 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans-N2- (4-aminocyclohexyl) -9- (1-ethylpropyl) -N6-propyl-9H-purin-2,6-diamine dihydrochloride.
  • Step 3 of Example 3 The procedure is as in Step 3 of Example 3 starting from 121 mg of the product obtained in Step 1 above and 489 mg of trans-1,4-diaminocyclohexane and is heated at a temperature of 140 to 150 ° C. for 4 hours. then cooled to 70-80 ° C and then diluted with 20 ml of water / ethyl acetate in a ratio of 50/50, decanted, washed with 10 ml of water and 5 ml of saturated aqueous sodium chloride, dry and evaporate to dryness.
  • PRODUCT 37 Trans-N2- (4-aminocyclohexyl) -9- (1-ethylpropyl) -N6-phenyl-9H-purin-2,6-diamine dihydrochloride. Step 1 : 2-chloro-9- (1-ethylpropyl) -N-phenyl-9H-purin-6-amine.
  • Step 2 of Example 3 The procedure is as in Step 2 of Example 3 starting from 200 mg (0.77 mmol) of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.088 ml (0.96 mmol) of aniline instead of benzylamine. It is stirred at ambient temperature and then brought to a temperature of 80 to 85 ° C. for 22 hours. Allowed to warm to room temperature, diluted with 4 ml of isopropanol, left for two days at a temperature of about 0 ° C and then filtered, washed with 10 ml of isopropanol and dried at a temperature of about 50 ° C. After purification on silica eluting with methylene chloride / ethyl acetate in a proportion of 90/10, 104 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans-N2- (4-aminocyclohexyl) -9- (1-ethylpropyl) -N6-phenyl-9H-purin-2,6-diamine dihydrochloride.
  • Step 3 of Example 3 The procedure is as in Step 3 of Example 3 starting from 97 mg of the product obtained in Stage 1 above and 350 mg of trans-1,4-diaminocyclohexane and heated at a temperature of 140 to 150 ° C for about 4 hours and then cooled to 70-80 ° C and then diluted with 20 ml of water / ethyl acetate in a 50/50 ratio, let settle, washed with 10 ml of water and 5 ml of saturated aqueous sodium chloride, dried and evaporated to dryness.
  • Step 1 N - [[2-chloro-9-cyclopentyl-9H-purin-6-yl] amino] -4-ethoxy-benzenesulfonamide.
  • Step 1 of Example 8 The procedure is as in Step 1 of Example 8 starting from 257 mg of the product obtained in Stage 1 of Example 1, 4 ml of dimethoxyethane (DME), 390 mg of cesium carbonate (Cs 2 CO 3 ) and 201 mg of 4-ethoxy-benzenesulfonamide instead of benzenesulfonamide and stir at a temperature about 100 ° C for about 2 hours 30 minutes. Allowed to warm to room temperature, acidified with 4 ml of 2N hydrochloric acid, extracted with 2 x 10 ml of ethyl acetate, dried, filtered and evaporated to dryness. It is impasted in 10 ml of ether and dried at room temperature. 325 mg of expected product are thus obtained in the form of beige crystals.
  • DME dimethoxyethane
  • Cs 2 CO 3 cesium carbonate
  • 4-ethoxy-benzenesulfonamide instead of benzenesulfonamide
  • Step 2 Trans-N- [2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] -4-ethoxy-benzenesulfonamide dihydrochloride.
  • the process is carried out as in Stage 2 of Example 8 and carries 400 mg of trans-1,4-diaminocyclohexane at a temperature of approximately 150 ° C., adds 295 mg of the product obtained in Stage 1 above and temperature for about 7 hours 30 minutes. Then it is allowed to return to room temperature. Chromatography on silica eluting with methylene chloride / methanol / ammonia in a ratio of 70/30/1 and 90/10/1 to purify the product. 10 ml of ethanol and 3 ml of 1.4 N hydrochloric acid / ethanol are then added, the mixture is evaporated to dryness and the residue is then impasted in 10 ml of ether and dried under vacuum at a temperature of approximately 60.degree. 146 mg of expected product are thus obtained in the form of beige crystals.
  • Step 1 4-Bromo-N - [[2-chloro-9-cyclopentyl-9H-purin-6-yl] amino] benzenesulfonamide.
  • Step 1 of Example 8 The procedure is as in Step 1 of Example 8 starting from 257 mg of the product obtained in Stage 1 of Example 1, 4 ml of dimethoxyethane (DME), 390 mg of cesium carbonate (Cs 2 CO 3 ) and 236 mg of 4-bromo-benzenesulfonamide in place of benzenesulfonamide and stirred at a temperature of about 100 ° C for about 2 hours 30 minutes. Allowed to warm to room temperature, acidified with 4 ml of 2N hydrochloric acid, extracted with 2 x 10 ml of ethyl acetate, dried, filtered and evaporated to dryness. It is impasted in 10 ml of ether and dried at room temperature. 226 mg of expected product are thus obtained in the form of beige crystals.
  • DME dimethoxyethane
  • Cs 2 CO 3 cesium carbonate
  • 4 mo-benzenesulfonamide 4-bromo-benzenesulfonamide in
  • Step 2 Trans-N- [2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] -4-bromo-benzenesulfonamide dihydrochloride.
  • the process is carried out as in Stage 2 of Example 8 and carries 228 mg of trans-1,4-diaminocyclohexane at a temperature of approximately 150 ° C., adds 182 mg of the product obtained in Stage 1 above and temperature for about 8 hours. Chromatography on silica eluting with methylene chloride / methanol / ammonia in a ratio of 80/20/1, then add 10 ml of ethanol, 4 ml of 1.4N hydrochloric acid / ethanol and leave overnight. It is then evaporated to dryness and pasted in 10 ml of ether and dried under vacuum at a temperature of approximately 60 ° C. This gives 74 mg of expected product in the form of crystals beige.
  • Step 1 N - [[2-chloro-9-cyclopentyl-9H-purin-6-yl] amino] -4-methyl-benzenesulfonamide.
  • Step 1 of Example 8 The procedure is as in Step 1 of Example 8 starting from 257 mg of the product obtained in Step 1 of Example 1, 4 ml of dimethoxyethane (DME), 390 mg of cesium carbonate (CS 2 CO 3 ) and 171 mg of 4-methyl-benzenesulfonamide in place of benzenesulfonamide and stirred at a temperature of about 100 ° C for about 2 hours 30 minutes. Allowed to warm to room temperature, acidified with 4 ml of 2N hydrochloric acid, extracted with 2 x 10 ml of ethyl acetate, dried, filtered and evaporated to dryness. It is impasted in 10 ml of ether and dried at room temperature. In this way 292 mg of expected product is obtained in the form of beige crystals.
  • DME dimethoxyethane
  • CS 2 CO 3 cesium carbonate
  • Step 2 Trans-N- [2 - ((4-Aminocyclohexyl) -aminol-9-cyclopentyl-9H-purin-6-yl] -4-methyl-benzenesulfonamide dihydrochloride.
  • Step 2 of Example 8 The procedure is as in Step 2 of Example 8 and carries 285 mg of trans-1,4-diaminocyclohexane, at a temperature of about 150 ° C., 196 mg of the product obtained in Step 1 above is added and maintained at this temperature. temperature for about 7 hours. Chromatography on silica eluting with methylene chloride / methanol / ammonia in a proportion of 80/20/1, then add 8 ml of ethanol, 4 ml of 1.4N hydrochloric acid / ethanol and leave overnight. It is then evaporated to dryness and pasted in 10 ml of ether and dried under vacuum at a temperature of approximately 60 ° C. In this way 112 mg of expected product is obtained in the form of beige crystals.
  • PRODUCT 41 Trans-N2- (4-aminocyclohexyl-9- (1-ethylpropyl) -N6 - [(3-iodophenyl) methyl] -9H-purin-2,6-diamine dihydrochloride.
  • Step 1 2-chloro-9- (1-ethylpropyl) -N - [(3-iodophenyl) methyl) -9H-purin-6-amine.
  • Step 2 of Example 3 The procedure is as in Step 2 of Example 3 starting from 200 mg of the product obtained in Step 1 of Example 3 and 4 ml of butanol and using 0.123 ml of 3-iodobenzenemethanamine. instead of benzylamine. It is stirred at ambient temperature and then brought to a temperature of 80 to 85 ° C. for 22 hours. Allowed to warm to room temperature, diluted with 4 ml of isopropanol, left for three hours at a temperature of about 0 ° C and then filtered, washed with 10 ml of isopropanol and dried at a temperature of about 50 ° C. After purification on silica eluting with cyclohexane / ethyl acetate / methylene chloride in a proportion of 70/15/15, 235 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans-N2- (4-aminocyclohexyl-9- (1-ethylpropyl) -N6 - [(3-iodophenyl) methyl] -9H-purin-2,6-diamine dihydrochloride.
  • Step 3 of Example 3 The procedure is as in Step 3 of Example 3 starting from 226 mg of the product obtained in Step 1 above and 565 mg of trans-1,4-diaminocyclohexane and is heated at a temperature of 140 to 150 ° C. for 4 hours. then cooled to 70-80 ° C and then diluted with 20 ml of water / ethyl acetate in a ratio of 50/50, decanted, washed with 10 ml of water and 5 ml of saturated aqueous sodium chloride, dry and evaporate to dryness.
  • PRODUCT 42 Trans-N2- (4-aminocyclohexyl) -9- (1-ethylpropyl) -N6- [4- (trifluoromethoxy) -phenyl] -9H-purin-2,6-diamine dihydrochloride.
  • Step 1 2-chloro-9- (1-ethylpropyl) -N- [4- (trifluoromethoxy) -phenyl] -9H-purin-6-amine.
  • Step 2 of Example 3 The procedure is as in Step 2 of Example 3 starting from 200 mg of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.13 ml of 4- (trifluoromethoxy) -benzenamine instead. benzylamine. It is stirred at ambient temperature and then brought to a temperature of 80 to 85 ° C. for 22 hours. Allowed to warm to room temperature, diluted with 4 ml of isopropanol, left for four hours at a temperature of about 0 ° C and then filtered, washed with 10 ml of isopropanol and dried at a temperature of about 50 ° C. After purification on silica eluting with cyclohexane / ethyl acetate / methylene chloride in a proportion of 70/15/15, 169 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans-N2- (4-aminocyclohexyl) -9- (1-ethylpropyl) -N6- [4- (trifluoromethoxy) -phenyl] -9H-purin-2,6-diamine dihydrochloride.
  • Step 3 of Example 3 The procedure is as in Step 3 of Example 3 starting from 160 mg of the product obtained in Step 1 above and 456 mg of trans-1,4-diaminocyclohexane and is heated at a temperature of 140 to 150 ° C. for 4 hours. then cooled to 70-80 ° C and then diluted with 20 ml of water / ethyl acetate in a proportion of 50/50 decanted, washed with 10 ml of water and 5 ml of sodium chloride. sodium in saturated aqueous solution, dry and evaporate to dryness.
  • PRODUCT 43 Ethyl trans-4 - [[2 - [(4-aminocyclohexyl) amino] -9- (1-ethylpropyl) -9H-purin-6-yl] -amino] -benzoate dihydrochloride.
  • Step 1 4 - Ethyl [[2-chloro-9- (1-ethylpropyl) -9H-purin-6-yl] amino] benzoate.
  • Step 2 of Example 3 The procedure is as in Step 2 of Example 3 starting from 200 mg of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 158 mg of ethyl 4-aminobenzoate instead of benzylamine. . It is stirred at ambient temperature and then brought to a temperature of 80 to 85 ° C. for 22 hours. Allowed to warm to room temperature, diluted with 4 ml of isopropanol, left for two days at a temperature of about 0 ° C and then filtered, washed with 10 ml of isopropanol and dried at a temperature of about 50 ° C. After purification on silica with eluent methylene chloride / ethyl acetate in a proportion of 90/10, 209 mg of expected product is obtained in the form of white crystals.
  • Step 2 Ethyl trans-4 - [[2 - [(4-aminocyclohexyl) amino] -9- (1-ethylpropyl) -9H-purin-6-yl] -amino] -benzoate dihydrochloride
  • Step 3 of Example 3 The procedure is as in Step 3 of Example 3 starting from 198 mg of the product obtained in Step 1 above and 582 mg of trans-1,4-diaminocyclohexane and is heated at a temperature of 140 to 150 ° C. for 4 hours. then cooled to 70-80 ° C and then diluted with 20 ml of water / ethyl acetate in a ratio of 50/50, decanted, washed with 10 ml of water and 5 ml of saturated aqueous sodium chloride, dry and evaporate to dryness.
  • PRODUCT 44 Trans (+ -) - N2- (4-aminocyclohexyl) -N6 - [(3-iodophenyl) methyl] -9- (1-methylpropyl) -9H-purin-2,6-diamine dihydrochloride.
  • Step 1 (+ -) - 2-chloro-N - [(3-iodophenyl) methyl] -9- (1-methylpropyl) -9H-purin-6-amine.
  • Step 2 of Example 9 The procedure is as in Step 2 of Example 9 from 200 mg of the product obtained in Step 1 of Example 9 and 4 ml of butanol and using 0.128 ml of 3-iodobenzememethanamine instead of benzylamine. It is heated at 80 to 85 ° C for about 22 hours. Allowed to warm to room temperature, diluted with 4 ml of isopropanol and placed two days at a temperature of about 0 ° C. Then it is drained, washed with 10 ml of isopropanol and dried at a temperature of about 50 ° C. After purification on silica eluting with methylene chloride / ethyl acetate in a proportion of 90/10, 290 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -N6 - [(3-iodophenyl) methyl] -9- (1-methylpropyl) -9H-purin-2,6-diamine dihydrochloride.
  • Step 3 of Example 9 The procedure is as in Step 3 of Example 9 starting from 279 mg of the product obtained in Step 1 above and 720 mg of trans-1,4-diaminocyclohexane. After purification under the same conditions as for Example 9, salified with 10 ml of 1.4N HCl / ethanol and evaporated to dryness. This gives 232 mg of expected product in the form of crystals.
  • Step 1 2 Ethyl [[[2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -amino] -sulfonyl] -benzoate.
  • Step 1 of Example 10 The procedure is as in Step 1 of Example 10 starting from 280 mg of the product obtained in Step 1 of Example 7, 4 ml of methylene chloride, 0.2 ml of triethylamine and 400 mg of 2- (chlorosulfonyl). methyl benzoate in place of 4-methyl-benzenesulfonic acid chloride and then stirred at room temperature for about 30 minutes. 5 ml of water are then added, extracted with methylene chloride (2 ⁇ 10 ml), washed with 5 ml of H 2 O, dried and evaporated. After chromatography on silica eluting with methylene chloride / ethyl acetate in a proportion of 70/30, 129 mg of expected product is thus obtained.
  • Step 2 Trans-N- (4-aminocyclohexyl) -2 - [[[2 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] -amino trihydrochloride ] ethyl] -amino sulfonyl] -benzamide.
  • Step 2 of Example 10 The procedure is as in Step 2 of Example 10 starting from 111 mg of the product obtained in Step 1 above and 262 mg of trans-1,4-diaminocyclohexane and heating at about 140 ° C for about 3 hours and then down at 80 ° C., then add 5 ml AcOEt then 10 ml of water to warm, allow to return to room temperature, extracted with 2 x 10 ml of ethyl acetate, washed with 10 ml of saturated aqueous sodium chloride solution and then dried.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -trifluoromethanesulfonamide.
  • Step 1 of Example 10 The procedure is as in Step 1 of Example 10 starting from 280 mg of the product obtained in Step 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of triethylamine, 0.128 ml of acid chloride. trifluoromethanesulfonic acid instead of 4-methyl-benzenesulfonic acid chloride and then stirred at room temperature for about 30 minutes. Then 2 ml of water, extracted with 3 x 5 ml of methylene chloride, washed with 5 ml of saturated sodium chloride, dried and evaporated. It is impasted with 5 ml of ether and then with 5 ml of pentane wring, and dried. 315 mg of expected product is thus obtained in the form of a beige solid.
  • Step 2 Trans-N- (2 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] ethyl] -trifluoromethanesulfonamide dihydrochloride.
  • Step 2 of Example 10 The procedure is as in Step 2 of Example 10 starting from 292 mg of the product obtained in Step 1 above and 810 mg of trans-1,4-diaminocyclohexane and heating at about 140 ° C for about 3 hours and then down to 80 ° C., add 5 ml of AtOEt then 10 ml of hot water, allow to return to room temperature, extract with 2 ⁇ 10 ml of ethyl acetate, wash with 10 ml of saturated sodium chloride, and dry.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -4-fluoro-benzenesulfonamide.
  • Step 1 of Example 10 The procedure is as in Step 1 of Example 10 starting from 280 mg of the product obtained in Step 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of triethylamine and 0.128 ml of acid chloride. 4-fluorobenzene sulfonic acid instead of 4-methyl-benzenesulfonic acid chloride and stirred at room temperature for about 30 minutes. Then 2 ml of water, extracted with 3 x 5 ml of methylene chloride, washed with 5 ml of saturated sodium chloride, dried and evaporated. It is impasted with 5 ml of ether and then with 5 ml of pentane wring, and dried. 360 mg of expected product is thus obtained.
  • Step 2 Trans-4 - [(4-aminocyclohexyl) amino] -N- [2 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] trihydrochloride - amino] ethyl] -benzenesulfonamide.
  • Step 2 of Example 10 The procedure is as in Step 2 of Example 10 from 173 mg of the product obtained in Step 1 above and 450 mg of trans-1,4-diaminocyclohexane and heated to about 140 ° C for about 3 hours then allow to return to 80 ° C, add 5 ml AcOEt then 5 ml of hot water. Allowed to warm to room temperature, extracted with 2 x 10 ml of ethyl acetate, washed with 10 ml of saturated sodium chloride and dried.
  • Step 1 N - [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -4- (trifluoromethyl) -benzenesulfonamide.
  • Step 1 of Example 10 The procedure is as in Step 1 of Example 10 starting from 280 mg of the product obtained in Step 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of triethylamine and 280 mg of acid chloride. 4- (trifluoromethyl) -benzenesulfonic acid instead of 4-methylbenzenesulfonic acid chloride, and then stirred at room temperature for about 30 minutes. Then 2 ml of water, extracted with 3 x 5 ml of methylene chloride, washed with 5 ml of saturated sodium chloride, dried and evaporated. It is impasted with 5 ml of ether and then with 5 ml of pentane, drained and dried. In this way 375 mg of expected product is obtained.
  • Step 2 Trans-N- (2 - [[2 - [[4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] ethyl] -4- (trifluoromethyl) dihydrochloride benzenesulfonamide.
  • Step 2 of Example 10 The procedure is as in Step 2 of Example 10 from 188 mg of the product obtained in Step 1 above and 440 mg of trans-1,4-diaminocyclohexane and heated at about 140 ° C for about 3 hours. Allowed to return to 80 ° C, add 5 ml of AcOEt then 5 ml of hot water. Allowed to warm to room temperature and extracted with 2 x 5 ml of ethyl acetate, washed with 5 ml of saturated sodium chloride, and then dried.
  • PRODUCT 49 Trans (+ -) - N2- (4-aminocyclohexyl) -9- (1-methylpropyl) -N6-propyl-9H-purin-2,6-diamine dihydrochloride.
  • Step 1 (+ -) - 2-chloro-9- (1-methylpropyl) -N-propyl-9H-purin-6-amine.
  • Step 2 of Example 9 The procedure is as in Step 2 of Example 9 from 200 mg of the product obtained in Step 1 of Example 9 and 4 ml of butanol and using 0.132 ml 1-propanamine instead of benzylamine. It is stirred at room temperature and then brought to a temperature of 80 to 85 ° C for about 22 hours. It is allowed to return to room temperature. It is taken up in 5 ml of ethyl acetate and evaporated to dryness. It is impregnated at room temperature in 5 ml of pentane, filtered off, washed with 5 ml of pentane and dried at a temperature of approximately 50 ° C. After purification on silica eluting with methylene chloride / ethyl acetate in a proportion of 90/10, 203 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -9- (1-methylpropyl) -N6-propyl-9H-purin-2,6-diamine dihydrochloride.
  • Step 2 of Example 44 The procedure is as in Step 2 of Example 44 starting from 117 mg of the product obtained in Step 1 above and 500 mg of trans-1,4-diaminocyclohexane. In this way 80 mg of expected product is obtained in the form of crystals.
  • PRODUCT 50 Trans (+ -) - N2- (4-aminocyclohexyl)) - 9- (1-methylpropyl) -N6- [4- (trifluoromethoxy) -phenyl] -9H-purin-2,6-diamine dihydrochloride.
  • Step 1 (+ -) - 2-chloro-9- (1-methylpropyl) -N- [4- (trifluoromethoxy) -phenyl] -9H-purin-6-amine.
  • Step 2 of Example 9 The procedure is as in Step 2 of Example 9 starting from 200 mg of the product obtained in Step 1 of Example 9 and 4 ml of butanol and using 0.135 ml of 4- (trifluoromethoxy) -benzenamine in place of the benzylamine. It is stirred at room temperature and then brought to a temperature of 80 to 85 ° C for about 22 hours. Allowed to warm to room temperature, diluted with 4 ml of isopropanol and placed two days at a temperature of about 0 ° C. Then it is filtered, washed with 5 ml of isopropanol and dried at a temperature of about 50 ° C. After purification on silica eluting with methylene chloride / ethyl acetate in a proportion of 90/10, 210 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -9- (1-methylpropyl) -N6- [4- (trifluoromethoxy) -phenyl] -9H-purin-2,6-diamine dihydrochloride.
  • Step 2 of Example 44 The procedure is as in Step 2 of Example 44 starting from 201 mg of the product obtained in Step 1 above and 595 mg of trans-1,4-diaminocyclohexane. 139 mg of expected product are thus obtained in the form of crystals.
  • PRODUCT 51 Ethyl trans (+ -) - 4 - [[2 - [[4-aminocyclohexyl) amino] -9- (1-methylpropyl) -9H-purin-6-yl] amino] benzoate dihydrochloride .
  • Step 1 (+ -) - 4 - [[2-chloro-9- (1-methylpropyl) -9H-purin-6-yl] amino] benzoate.
  • Step 2 of Example 9 The procedure is as in Step 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.165 mg of ethyl 4-aminobenzoate in place of benzylamine. . It is stirred at room temperature and then brought to a temperature of 80 to 85 ° C for about 22 hours. Allowed to warm to room temperature, diluted with 4 ml of isopropanol and placed two days at a temperature of about 0 ° C. Then it is filtered, washed with 5 ml of isopropanol and dried at a temperature of about 50 ° C. After purification on silica eluting with methylene chloride / ethyl acetate in a proportion of 90/10, 289 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans (+ -) - 4 - [[2 - [[4-aminocyclohexyl) -amino] -9- (1-methylpropyl) -9H-purin-6-yl] -amino] -benzoate dihydrochloride ethyl.
  • PRODUCT 52 Trans (+ -) - N2- (4-aminocyclohexyl) -9- (1-methylpropyl) -N6-phenyl-9H-purin-2,6-diamine dihydrochloride.
  • Step 1 (+ -) - 2-chloro-9- (1-methylpropyl) -N-phenyl-9H-purin-6-amine.
  • Step 2 of Example 9 The procedure is as in Step 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.091 ml of aniline at place benzylamine. It is stirred at room temperature and then brought to a temperature of 80 to 85 ° C for about 22 hours. Allowed to warm to room temperature, diluted with 4 ml of isopropanol and placed two days at a temperature of about 0 ° C. Then it is filtered off, washed with 5 ml of isopropanol and dried at a temperature of about 80 ° C. After purification on silica eluting with methylene chloride / ethyl acetate in a proportion of 90/10, 176 mg of expected product are obtained in the form of white crystals.
  • Step 2 Trans (+ -) - N2- (4-aminocyclohexyl) -9- (1-methylpropyl) -N6-phenyl-9H-purin-2,6-diamine dihydrochloride.
  • Step 2 of Example 44 The procedure is as in Step 2 of Example 44 starting from 166 mg of the product obtained in Step 1 above and 629 mg of trans-1,4-diaminocyclohexane. In this way 158 mg of expected product is obtained in the form of crystals.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -4-methoxy-benzenesulfonamide.
  • Step 1 of Example 10 The procedure is as in Step 1 of Example 10 starting from 280 mg of the product obtained in Step 1 of Example 7, 4 ml of methylene chloride, 0.2 ml of triethylamine and 248 mg of acid chloride. 4-methoxybenzenesulfonic acid instead of 4-methylbenzenesulfonic acid chloride and then stirred at room temperature for about one night. Then 2 ml of water, extracted with 3 x 5 ml of methylene chloride, washed with 5 ml of saturated sodium chloride, dried and evaporated. It is impasted with 5 ml of ether and then with 5 ml of pentane, drained and dried. After chromatography on silica eluting with methylene chloride / CH 3 CN in a proportion of 70/30, 250 mg of expected product is thus obtained in the form of a beige solid.
  • Step 2 Trans-N- [2 - [[2 - [(4-aminocyclohexyl) -amino] -9-cyclopentyl-9H-purin-6-yl] -amino] -ethyl] -4-methoxy-benzenesulfonamide dihydrochloride .
  • Step 2 of Example 10 The procedure is as in Step 2 of Example 10 starting from 126 mg of the product obtained in Step 1 above and 319 mg of trans-1,4-diaminocyclohexane and heating at about 140 ° C for about 3 hours. Allowed to return to 80 ° C, add 5 ml AcOEt, add 5 ml of hot water. Allowed to warm to room temperature, extracted with 2 x 5 ml of ethyl acetate, washed with 5 ml of saturated sodium chloride and dried.
  • Step 1 4-chloro-N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -benzenesulfonamide.
  • Step 1 of Example 10 The procedure is as in Step 1 of Example 10 starting from 280 mg of the product obtained in Step 1 of Example 7, 4 ml of methylene chloride, 0.2 ml of triethylamine and 255 mg of acid chloride. 4-chlorobenzenesulfonic acid instead of 4-methyl-benzenesulfonic acid chloride and then stirred at room temperature for 30 minutes. Then 2 ml of water, extracted with 3 x 5 ml of methylene chloride, washed with 5 ml of saturated sodium chloride, dried and evaporated. It is impasted with 5 ml of ether and then with 5 ml of pentane, drained and dried. After chromatography on silica eluting with methylene chloride / CH 3 CN in a proportion of 70/30, 350 mg of expected product in the form of beige solid.
  • Step 2 Trans-N- [2 - [[2 - [(4-aminocyclohexyl) -amino] -9-cyclopentyl-9H-purin-6-yl] -amino] -ethyl] -4-chloro-benzenesulfonamide dihydrochloride .
  • Step 2 of Example 10 The procedure is as in Step 2 of Example 10 from 161 mg of the product obtained in Step 1 above and 403 mg of trans-1,4-diaminocyclohexane and heated at about 140 ° C for about 3 hours 30 minutes. Allowed to return to 80 ° C, add 5 ml of AcOEt then 5 ml of hot water. Allowed to warm to room temperature, extracted with 2 x 5 ml of ethyl acetate, washed with 5 ml of saturated sodium chloride and dried.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -1-methyl-ethanesulfonamide.
  • Step 2 Trans-N- [2- [2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] ethyl] -1-methyl-ethanesulfonamide dihydrochloride.
  • Step 2 of Example 10 The procedure is as in Step 2 of Example 10 from 157 mg of the product obtained in Step 1 above and 315 mg of trans-1,4-diaminocyclohexane and heated at about 140 ° C for about 3 hours 30 minutes. Go down to 80 ° C, add 5 ml AcOEt, add 5 ml of hot water. Allowed to warm to room temperature, extracted with 2 x 5 ml of ethyl acetate, washed with 5 ml of saturated sodium chloride and dried.
  • Step 1 of Example 45 The procedure is as in Step 1 of Example 45 using instead of 2- (chlorosulfonyl) -benzoate methyl, O-chlorosulfonyl-ethyl benzoate. From the product thus obtained, the procedure is as in Step 2 of Example 45 and thus provides the expected product.
  • Stage 1 Methyl 3 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) amino] benzoate.
  • Step 1 of Example 6 The procedure is as in Step 1 of Example 6 by introducing at room temperature 257 mg of the product obtained in Stage 1 of Example 1, 4 ml of butanol and 181 mg of methyl-3-aminobenzoate and is heated to a temperature of about 100 ° C for about 5 hours. Evaporate, dust with ether and dry. 352 mg of expected product are thus obtained in the form of off-white crystals.
  • Step 2 Trans-3 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] benzoic acid dihydrochloride.
  • Step 2 of Example 6 The procedure is as in Step 2 of Example 6 and carries 400 mg of trans-1,4-diaminocyclohexane at a temperature of about 150 ° C. and 260 mg of the product obtained in Stage 1 above are added: the mixture is left stirring. for 5 hours then leave overnight at room temperature. 5 ml of water are then added, the mixture is extracted with 40 ml of ethyl acetate, 10 ml of methanol are added, the mixture is dried, filtered and evaporated to dryness. It is taken up in 4 ml of 1.4N HCl in ethanol and 20 ml of methanol, evaporated to dryness and then impasted in 5 ml of ether and dried at a temperature of about 60 ° C. 73 mg of expected product is thus obtained in the form of a beige solid.
  • Step 2 Ethyl trans-3 - [[2 - [(4-aminocyclohexyl) -amino] -9-cyclopentyl-9H-purin-6-yl] amino] benzoate dihydrochloride
  • Trans-1,4-diaminocyclohexane 400 mg is heated at about 140 ° C. and then 270 mg of the product obtained in Stage 1 above are added, the mixture is left stirring for 5 hours and then allowed to return to ambient temperature. 15 ml of water are then added, the mixture is extracted with dichloromethane, washed with water, dried, the solvents are evaporated, the residue is chromatographed on silica with methanol / ammonia (98/2) as eluent and the residue is taken up in ethanol. It is salified with a solution of HCl in 1.4N EtOH and dried at a temperature of about 60 ° C the expected hydrochloride. 156 mg of expected product is thus obtained.
  • Step 1 4 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) amino] benzamide.
  • Step 1 of Example 6 The procedure is as in Step 1 of Example 6, introducing at room temperature 193 mg of the product obtained in Stage 1 of Example 1, 2 ml of butanol and 68 mg of 4-aminobenzamide and is stirred at a temperature of approximately 100.degree. ° C for about 20 hours. Evaporate, dust with ether and dry. In this way 170 mg of expected product is obtained in the form of crystals.
  • Step 2 Trans-4 - ((2 - ((4-aminocyclohexyl) amino) -9-cyclopentyl-9H-purin-6-yl) amino) -benzamide dihydrochloride.
  • Example 6 The procedure is as in Example 6, using in Stage 1 of Example 6 in place of ethyl-4-aminobenzoate, 3-methylaminobenzamide. Proceeding as in Step 2 of Example 6, the expected product is thus obtained.
  • Example 1 The procedure is as in Example 1 using in step 2 of Example 1 in place of the methyl 4- (aminomethyl) -benzoate hydrochloride, methyl 3- (aminomethyl) -benzoate hydrochloride.
  • Step 1 N - [[2-chloro-9-cyclopentyl-9H-purin-6-yl] amino] -3-pyridinesulfonamide
  • Step 1 of Example 8 The procedure is as in Step 1 of Example 8 starting from 514 mg of the product obtained in Stage 1 of Example 1, 8 ml of dimethoxyethane (DME), 780 mg of cesium carbonate (CS 2 CO 3 ) and 316 mg of 3-pyridinesulfonamide in place of benzenesulfonamide and stirred at a temperature of about 100 ° C for about 5 hours 30 minutes and left overnight at room temperature. 4 ml of 2N hydrochloric acid are then added, the precipitate formed is filtered off, rinsed with 5 ml of water and dried under vacuum at a temperature of approximately 50.degree. This gives 414 mg of expected product in the form of beige crystals.
  • DME dimethoxyethane
  • CS 2 CO 3 cesium carbonate
  • 3-pyridinesulfonamide 3-pyridinesulfonamide in place of benzenesulfonamide
  • Step 2 Trans-N- (2 - (((4-Aminocyclohexyl) amino) -9-cyclopentyl-9H-purin-6-yl) -3-pyridine sulfonamide dihydrochloride.
  • Step 2 of Example 8 The procedure is as in Step 2 of Example 8 and carries 400 mg of trans-1,4-diaminocyclohexane, at a temperature of about 140 ° C., 265 mg of the product obtained in Step 1 above is added and maintained at this temperature. temperature for about 3 hours 30 minutes. Chromatography on silica eluting with methanol / ammonia in a proportion of 98/2, then adding 4 ml of ethanol and 2 ml of methanol and then 4 ml of 1.4N hydrochloric acid / ethanol, filter the insoluble light and then evaporate to dryness. , paste in 10 ml of ether and dried under vacuum at a temperature of about 60 ° C. 148 mg of expected product are thus obtained in the form of brown crystals.
  • Example 1 The procedure is as in Example 1 using in step 2 of Example 1 in place of the methyl 4- (amino-methyl) -benzoate hydrochloride, ethyl ⁇ -aminobutyrate and then proceed as in Step 3 of Example 1 from the product thus obtained.
  • EXAMPLE 66 Ethyl trans-4 - [[2 - [(4-aminocyclohexyl) methylamino] -9-cyclopentyl-9H-purin-6-yl] amino] benzoate dihydrochloride.
  • Example 65 The product of Example 65 is used, deprotecting the N-BOC amine by the action of trifluoroacetic acid. The expected product is thus obtained.
  • Example 1 The procedure is as in Example 1, using in Step 2 of Example 1 instead of methyl 4- (amino-methyl) benzoate hydrochloride, benzylamine and in Step 3 of Example 1, the 1 methyl-trans-1,4 aminocyclohexanol instead of trans 1-4 diaminocyclohexane.
  • Example 1 The procedure is as in Example 1 using in Step 2 of Example 1 in place of the methyl 4- (amino-methyl) benzoate hydrochloride, benzylamine and in Step 3 of Example 1 the 2- hydroxy-trans-1,4-diaminocyclohexane instead of trans 1-4 diaminocyclohexane.
  • Example 1 The procedure is as in Example 1 using in Step 2 of Example 1 in place of the methyl 4- (amino-methyl) benzoate hydrochloride, benzylamine and in Step 3 of Example 1, the 3 -hydroxy-trans-1,4-diaminocyclohexane in place of trans 1-4 diaminocyclohexane.
  • Example 1 The procedure is as in Example 1 using in Step 2 of Example 1 in place of the methyl 4- (amino-methyl) benzoate hydrochloride, benzylamine and in Step 3 of Example 1, the 3 -fluoro-trans-1,4-diaminocyclohexane in place of trans 1-4 diaminocyclohexane.
  • Example 1 The procedure is as in Example 1 using in Step 2 of Example 1 in place of the methyl 4- (amino-methyl) benzoate hydrochloride, benzylamine and in Step 3 of Example 1, the trans-1,4-diaminocyclohexane, trans-1,4-Bocaminocyclohexanol in the presence of sodium hydride (NaH) in dimethylformamide.
  • NaH sodium hydride
  • EXAMPLE 72 4 - [[9-Cyclopentyl-6 - [(phenyl-methyl) amino] -9H-purin-2-yl] amino] -cyclohexanone dihydrochloride.
  • Example 4 From the product of Example 4 is carried out by oxidation in DMF in the presence of (PDC) pyridinium dichromate, and the expected product is obtained after filtration through silica with CH 2 Cl 2 / methanol: 80/20 as eluent.
  • PDC pyridinium dichromate
  • Example 72 From the product of Example 72 is carried out by reaction with O-methylhydroxylamine in ethanol under reflux and the expected product is thus obtained.
  • Step 1 2-Chloro-9-cyclopentyl-N- [2 - [[(3,4-dichlorophenyl) methyl] amino] ethyl] -9H-purin-6-amine.
  • Step 2 trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [2 - [[(3,4-dichlorophenyl) methyl] amino] ethyl] -9H-purine-2,6-trifluorohydrochloride diamine.
  • Step 1 2-chloro-9-cyclopentyl-N- [2 - [[[4- (trifluoromethoxy) -phenyl] -methyl] -amino] -ethyl] -9H-purin-6-amine.
  • Step 2 trans-N2- (4-Aminocyclohexyl) -9-cyclopentyl-N6- [2 - [[[4- (trifluoromethoxy) -phenyl] -methyl] -amino] -ethyl] -9H-purine-2-trihydrochloride , 6-diamine.
  • Step 1 2-Chloro-9-cyclopentyl-N- [2 - [[(3,5-dichlorophenyl) methyl] amino] ethyl] -9H-purin-6-amine.
  • Step 2 trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [2 - [[(3,5-dichlorophenyl) methyl] amino] ethyl] -9H-purine-2,6-trihydrochloride diamine.
  • Step 1 2-chloro-9-cyclopentyl-N- [2 - [[(4-fluorophenyl) methyl] amino] ethyl] -9H-purin-6-amine.
  • Step 2 trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [2 - [[(4-fluorophenyl) -methyl] -amino] -ethyl] -9H-purine-2,6-diamine trihydrochloride .
  • Step 1 2-Chloro-9-cyclopentyl-N- [2 - [[[4- (trifluoromethyl) -phenyl] -methyl] -amino] -ethyl] -9H-purin-6-amine.
  • Step 2 trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [2 - [[[4- (trifluoromethyl) -phenyl] -methyl] -amino] -ethyl] -9H-purine-2-trihydrochloride , 6-diamine.
  • Step 1 2-chloro-N- [2 - [[(3-chlorophenyl) methyl] amino] ethyl] -9-cyclopentyl-9H-purin-6-amine.
  • Step 2 trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [2 - [[(3-chlorophenyl) -methyl] -amino] -ethyl] -9H-purine-2,6-diamine trihydrochloride .
  • Step 1 2-Chloro-N - [(1,1'-biphenyl) -4-yl] -9-cyclopentyl-9H-purin-6-amine.
  • Step 2 Trans-N2- (4-aminocyclohexyl) -N6 - [(1,1'-biphenyl) -4-yl] -9-cyclopentyl-9H-purin-2,6-diamine dihydrochloride.
  • Trans-1,4-diaminocyclohexane (342 mg) is heated at about 150 ° C. and then 234 mg of the product obtained in Stage 1 above is added, the mixture is stirred at 140 ° C. for 9 hours 30 minutes and then allowed to return to ambient temperature. 10 ml of water are then added, the mixture is extracted with dichloromethane, dried, the solvent is evaporated off, the residue is chromatographed on silica (eluent: MeOH / NH 4 OH 98/2), taken up in 5 ml of ethanolic solution of hydrochloric acid and evaporated. solvents, impregnates the residue in the ether, dried under reduced pressure at 60 ° C and recovered 93 mg of expected product.
  • Step 1 4 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -benzeneacetonitrile.
  • Step 2 trans-4 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] benzeneacetonitrile dihydrochloride.
  • Step 1 2-chloro-9-cyclopentyl-N- [4- (4-morpholinyl) phenyl] -9H-purin-6-amine.
  • Step 2 trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [4- (4-morpholinyl) -phenyl] -9H-purin-2,6-diamine dihydrochloride.
  • Step 1 4 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) amino] benzonitrile.
  • Step 2 trans-4 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] benzonitrile dihydrochloride.
  • Step 1 2-chloro-9-cyclopentyl-N- (4-nitrophenyl) -9H-purin-6-amine.
  • Step 2 trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- (4-nitrophenyl) -9H-purin-2,6-diamine dihydrochloride.
  • Step 1 2-Chloro-9-cyclopentyl-N- [4- (trifluoromethyl) phenyl] -9H-purin-6-amine.
  • Step 2 Trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- [4- (trifluoromethyl) -phenyl] -9H-purin-2,6-diamine dihydrochloride.
  • Hydrogen is hydrogenated for 16 hours at room temperature, 455 mg of product obtained as in Example 84 in 10 ml of tetrahydrofuran in the presence of 230 mg of active palladium on carbon.
  • the mixture is filtered, rinsed with tetrahydrofuran, the solvent is evaporated, the residue is chromatographed on silica (eluent: MeOH / NH 4 OH 98/2), taken up in 10 ml of ethanol, 4 ml of ethanolic solution of hydrochloric acid are added, the mixture is filtered off, washed with ether, dried under reduced pressure at 60 ° C and recovered 338 mg of expected product.
  • Stage 1 2-chloro-9-cyclopentyl-N-phenyl-9H-purin-6-amine.
  • Step 2 trans-9-cyclopentyl-N2- (4-hydroxycyclohexyl) -N6-phenyl-9H-purin-2,6-diamine hydrochloride.
  • trans-1,4-aminocyclohexanol 575 mg are mixed and brought to a temperature of 50 to 60 ° C. and 313 mg of the product obtained in Stage 1 above are then added and the mixture is stirred at a temperature of 150 to 160 ° C. for about 20 hours.
  • the mixture is then allowed to return to room temperature, is taken up in ethyl acetate and water and is brought to a temperature of approximately 60.degree. It is then left to decant, reextracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried and evaporated to dryness.
  • Step 1 4 - Ethyl [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -benzoate.
  • Step 2 Ethyl trans-9-cyclopentyl-4 - [[2 - [(4-hydroxycyclohexyl) amino] -9H-purin-6-yl] amino] benzoate dihydrochloride.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -4- (trifluoromethyl) -benzamide.
  • Step 2 trans-N- [2 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] ethyl] -4- (trifluoromethyl) dihydrochloride -benzamide.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -4-methoxy-benzamide.
  • Step 2 Trans-N- [2 - [[2 - [(4-aminocyclohexyl) -amino] -9-cyclopentyl-9H-purin-6-yl] -amino] -ethyl] -4-methoxy-benzamide dihydrochloride .
  • Step 1 N - [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -3,5-dichlorobenzamide.
  • Step 2 trans-N- [2 - [[2 - [(4-aminocyclohexyl) -amino] -9-cyclopentyl-9H-purin-6-yl] -amino] -ethyl] -3,5-dichlorohydrochloride dihydrochloride -benzamide.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -4-chlorobenzamide.
  • Step 2 trans-N- [2 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] ethyl] -4-chlorobenzamide dihydrochloride .
  • Step 1 N - [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) amino] ethyl] -3,4-dichlorobenzamide.
  • Step 2 Trans-N- [2 - [[2 - [(4-aminocyclohexyl) -amino] -9-cyclopentyl-9H-purin-6-yl] -amino] -ethyl] -3,4-dichlorohydrochloride dihydrochloride -benzamide.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -3,4-dimethoxy-benzamide.
  • Step 2 Trans-N- [2 - [[2 - [(4-aminocyclohexyl) -amino] -9-cyclopentyl-9H-purin-6-yl] -amino] -ethyl] -3,4-dimethoxy dihydrochloride -benzamide.
  • Step 1 2-chloro-N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -4-nitro-benzamide.
  • Step 2 Trans-N- [2 - [[2 - [(4-aminocyclohexyl) -amino] -9-cyclopentyl-9H-purin-6-yl] -amino] -ethyl] -2-chloro-4-dihydrochloride nitro-benzamide.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl] amino] ethyl] -3,5-bis (trifluoromethyl) benzamide.
  • Step 2 Trans-N- [2 - [[2 - [(4-Aminocyclohexyl) -amino] -9-cyclopentyl-9H-purin-6-yl] -amino] -ethyl] -3,5-bis dihydrochloride (trifluoromethyl) benzamide.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -4- (methylthio) -benzamide.
  • Step 2 trans-N- [2 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] ethyl] -4- (methylthio) dihydrochloride -benzamide.
  • Step 1 N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -4-fluoro-benzamide.
  • Step 2 trans-N- [2 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] ethyl] -4-fluoro-benzamide dihydrochloride .
  • Step 1 N - [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -3- (trifluoromethyl) -benzamide.
  • Step 2 trans-N- [2 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] ethyl] -3- (trifluoromethyl) dihydrochloride -benzamide.
  • Step 1 N - [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -3- (trifluoromethoxy) -benzamide.
  • Step 2 trans-N- [2 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] ethyl] -3- (trifluoromethoxy) dihydrochloride -benzamide.
  • Step 1 3-chloro-N- [2 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -ethyl] -benzamide.
  • Step 2 Trans-N- [2 - [[2 - [(4-aminocyclohexyl) -amino] -3-chloro-9-cyclopentyl-9H-purin-6-yl] -amino] -ethyl] -benzamide dihydrochloride .
  • Step 1 4 - Ethyl [(2-chloro-9-cyclopentyl-9H-purin-6-yl) amino] benzeneacetate.
  • Step 2 Ethyl trans-4 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] benzeneacetate dihydrochloride.
  • Step 1 4 - [(2-Chloro-9-cyclopentyl-9H-purin-6-yl) amino] -N- (2-thiazolyl) benzenesulfonamide.
  • Step 2 trans-4 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] -N- (2-thiazolyl) benzenesulfonamide dihydrochloride.
  • Step 1 4 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -benzenesulfonamide.
  • Step 2 Trans-4 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] benzenesulfonamide dihydrochloride.
  • Trans-1,4-diaminocyclohexane 400 mg is heated at about 150 ° C. and then 275 mg of the product obtained in Step 1 above is added. The mixture is left stirring for 3 hours and then allowed to return to ambient temperature, the solvents are evaporated and the silica is chromatographed. (eluent: MeOH / NH 4 OH 98/2). The residue is taken up in an ethanolic solution of hydrochloric acid, the solvents are evaporated, the residue is spotted with ether, filtered off, dried under reduced pressure at ambient temperature and 205 mg of expected product is recovered.
  • Step 1 2-chloro-9-cyclopentyl-N- (4-methoxyphenyl) -9H-purin-6-amine.
  • Step 2 trans-N2- (4-aminocyclohexyl) -9-cyclopentyl-N6- (4-methoxyphenyl) -9H-purine-2,6-diamine dihydrochloride.
  • Trans-1,4-diaminocyclohexane 400 mg is heated at about 150 ° C. and then 172 mg of the product obtained is added. Stage 1 above. The mixture is stirred for 2 hours and then allowed to come to room temperature. The solvents are evaporated and the residue is chromatographed on silica (eluent: MeOH / NH 4 OH 98/2). The residue is taken up in an ethanolic solution of hydrochloric acid, the solvents are evaporated, the residue is spotted with ether, drained, dried under reduced pressure at room temperature and 188 mg of expected product is recovered.
  • EXAMPLE 106 Butyl trans-4 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] benzeneacetate dihydrochloride.
  • Stage 1 4 - [- [(2-Chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -benzeneacetate.
  • Step 2 trans-4 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] benzene-butyl acetate dihydrochloride.
  • Step 1 3 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -benzamide.
  • Step 2 trans-3 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] benzamide dihydrochloride.
  • Step 1 Diethyl 5 - [(2-chloro-9-cyclopentyl-9H-purin-6-yl) -amino] -1,3-benzenedicarboxylate.
  • Step 2 Diethyl trans-5 - [[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] -1,3-benzenedicarboxylate dihydrochloride.
  • EXAMPLE 110 Trans-5 - [[2 - [(4-Aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] -1,3-benzenedicarboxylic acid (disodium salt).
  • Step 2 Ethyl trans-3 - [[[2 - [(4-aminocyclohexyl) amino] -9-cyclopentyl-9H-purin-6-yl] amino] methyl] benzoate dihydrochloride.
  • trans-1,4-diaminocyclohexane 750 mg are brought to about 150 ° C. and then 375 mg of the product obtained in Stage 1 above are added, stirred at 140 ° C. for 5 hours 30 minutes and then allowed to return to ambient temperature. 5 ml of methanol are then added, chromatography on silica (eluent: MeOH / NH 4 OH 98/2, 314 mg of product is collected, and 67 mg of it in 4 ml of ethanolic solution of hydrochloric acid are evaporated off and the solvents are collected. mg of expected product.
  • Example 111 250 mg of the product obtained in Example 111 are introduced into ambient temperature at room temperature in 5 ml of ethanol and 0.6 ml of N sodium hydroxide are added. The mixture is stirred for 12 hours at room temperature, the solvents are evaporated off, the residue is washed with dry ether under reduced pressure at room temperature and collects 227 mg of expected product.

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WO2000071543A1 (fr) 2000-11-30
CZ20014163A3 (cs) 2002-10-16
US20050187228A1 (en) 2005-08-25
MA26791A1 (fr) 2004-12-20
AP2001002355A0 (en) 2001-12-31
EA005072B1 (ru) 2004-10-28
IL146441A0 (en) 2002-07-25
EA200101224A1 (ru) 2002-10-31
US7122669B1 (en) 2006-10-17
UA68441C2 (en) 2004-08-16
TWI284130B (en) 2007-07-21
AR035317A1 (es) 2004-05-12
CN1298719C (zh) 2007-02-07
EP1183256A1 (fr) 2002-03-06
KR20010113975A (ko) 2001-12-28
AP1477A (en) 2005-10-19
FR2793794A1 (fr) 2000-11-24
FR2793794B1 (fr) 2001-07-27
PL352293A1 (en) 2003-08-11
CA2374714A1 (fr) 2000-11-30
HUP0201649A3 (en) 2003-01-28
ATE370951T1 (de) 2007-09-15
JP2003500407A (ja) 2003-01-07
KR100707895B1 (ko) 2007-04-17
AU4764500A (en) 2000-12-12
NO20015659L (no) 2002-01-18
CN1361780A (zh) 2002-07-31
DE60036102T2 (de) 2008-05-15
ZA200109602B (en) 2003-01-29
YU86601A (sh) 2005-07-19
DZ3166A1 (fr) 2000-11-30
TR200103349T2 (tr) 2002-05-21
DK1183256T3 (da) 2007-12-03
PT1183256E (pt) 2007-11-13
US7208598B2 (en) 2007-04-24
NO20015659D0 (no) 2001-11-20
ES2290033T3 (es) 2008-02-16
SK16722001A3 (sk) 2003-01-09
DE60036102D1 (de) 2007-10-04
MXPA01011834A (es) 2002-04-17
NZ515556A (en) 2003-08-29
BR0011282A (pt) 2002-02-26

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